Human granulocyte colony-stimulating factor (G-CSF) is a glycoprotein having 204 amino acids with 30 amino-acid signal peptides. Mature G-CSF protein, having 18-20 kDa in molecular weight, is composed of 174 amino acids without signal peptides and secreted out of the cells. Human cells mainly responsible for such secretion are monocytes, fibroblasts, and endothelial cells.
There are three main biological functions for G-CSF, namely:
1. acting on myeloid precursors and stem cells to drive the differentiation, development, and maturation of neutrophils;
2. activating mature neutrophils to participate in immune response; and
3. acting with other hematopoietic growth factors such as stem cell factor, Flt-3 ligand, and GM-CSF to mobilize hematopoietic stem cells.
G-CSF receptor (G-CSFR) is proven to exist in bone marrow hematopoietic stem cells Sca+Lin−Th1low, precursor cells CD34+, committed granulocyte precursor cells, and mature neutrophils. G-CSFR is a specific receptor having a high affinity to G-CSF and 812 amino acids.
Tamada et al. obtained the crystalline structure of the G-CSF:G-CSFR complex and the stoichiometry of G-CSF:G-CSFR complex was shown as a 2:2 ratio by the 2.8 angstrom diffraction analysis (PNAS, 2008, Vol. 103: 3135-3140). In other words, in each complex, each G-CSF binds to one receptor chain to form a G-CSF-receptor complex when two G-CSF-receptor complexes are brought to close proximity, a 2:2 dimer is formed as a result of this interaction. Under this circumstance, the carboxyl terminal of the G-CSF receptor is then able to activate the downstream signal molecules JAKs (Janus tyrosine kinases, primarily JAK2). Consequently, JAK2 actives STAT3 to switch on the transcriptional genes which are critical for neutrophil differentiation and proliferation and activation.
In 2003, Schabitz W. R. et al. reported that recombinant human G-CSF (rhG-CSF) was shown to have a protective functionality on nerve cells from the study on the ischemic animal model (Storke, 2003, 34; 745-751). Later in 2006, Shyu et al. reported that rhG-CSF was shown to have clinical efficacy in the treatment of patients having acute stroke in which the patients were administrated with rhG-CSF daily for five consecutive days (CMAJ, 2006, 174:927-933). The in vivo half-life of rat G-CSF upon subcutaneous administration is about 2 hours, whereas the half-life of human G-CSF upon subcutaneous administration is only 3.5 hours. Therefore, it is required to administrate patients in need thereof with the drug daily, or intravenous infusion and this will affect the living quality of patients.